This invention relates to non-steroidal compounds that are modulators (i.e. agonists and antagonists) of androgen receptors, and to methods for the making and use of such compounds.
Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named xe2x80x9cligand dependent transcription factors.xe2x80x9d R. M. Evans, Science, 240:889 (1988). Steroid receptors are a recognized subset of the IRs, including the progesterone receptor (PR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand, which has the ability to selectively bind to the IR in a way that affects gene transcription.
Ligands to the IRs can include low molecular weight native molecules, such as the hormones progesterone, estrogen and testosterone, as well as synthetic derivative compounds such as medroxyprogesterone acetate, diethylstilbesterol and 19-nortestosterone. These ligands, when present in the fluid surrounding a cell, pass through the outer cell membrane by passive diffusion and bind to specific IR proteins to create a ligand/receptor complex. This complex then translocates to the cell""s nucleus, where it binds to a specific gene or genes present in the cell""s DNA. Once bound to DNA, the complex modulates the production of the protein encoded by that gene. In this regard, a compound that binds an IR and mimics the effect of the native ligand is referred to as an xe2x80x9cagonistxe2x80x9d, while a compound that inhibits the effect of the native ligand is called an xe2x80x9cantagonist.xe2x80x9d
Ligands to the steroid receptors are known to play an important role in health of both women and men. For example, the native female ligand, progesterone, as well as synthetic analogues, such as norgestrel (18-homonorethisterone) and norethisterone (17xcex1-ethinyl-19-nortestosterone), are used in birth control formulations, typically in combination with the female hormone estrogen or synthetic estrogen analogues, as effective modulators of both PR and ER. On the other hand, antagonists to PR are potentially useful in treating chronic disorders, such as certain hormone dependent cancers of the breast, ovaries, and uterus, and in treating non-malignant conditions such as uterine fibroids and endometriosis, a leading cause of infertility in women. Similarly, AR antagonists, such as cyproterone acetate and flutamide, have proved useful in the treatment of prostatic hyperplasia and cancer of the prostate.
The effectiveness of known modulators of steroid receptors is often tempered by their undesired side-effect profile, particularly during long-term administration. For example, the effectiveness of progesterone and estrogen agonists, such as norgestrel and diethylstilbesterol respectively, as female birth control agents must be weighed against the increased risk of breast cancer and heart disease to women taking such agents. Similarly, the progesterone antagonist, mifepristone (RU486), if administered for chronic indications, such as uterine fibroids, endometriosis and certain hormone-dependent cancers, could lead to homeostatic imbalances in a patient due to its inherent cross-reactivity as a GR antagonist. Accordingly, identification of compounds that have good specificity for one or more steroid receptors, but have reduced or no cross-reactivity for other steroid or intracellular receptors, would be of significant value in the treatment of male and female hormone responsive diseases.
A group of quinolinone and coumarin analogs having a fused ring system of the aryl, piperidine, pyrrolidine, or indoline series have been described as androgen modulators. See U.S. Pat. No. 5,696,130; Int. Patent Appl. WO 97/49709; L. G. Hamann, et. al. J. Med. Chem., 41:623-639 (1998); J. P. Edwards, et. al., Bioorg. Med. Chem. Lett., 8:745-750 (1998).
In addition, novel enantioselective synthetic routes to N-alkyl or N-aryl 3,4-dihydro-2H-1,4-benzoxazine compounds are described. Such compounds are key intermediates in the preparation of quinolinones and other fused ring structures of the instant invention. Often, when such fused-ring compounds are chiral and possess biological activity, only one enantiomer is biologically active, or the enantiomers possess different biological activity. Isolating and testing such enantiomers often yields a compound with enhanced selectivity, lower toxicity, and greater potency. Therefore, it would be highly advantageous to selectively prepare these types of compounds in the desired configuration. See Atarashi S., et al., J. Heterocyclic Chem., 28:329 (1991); Xie, L. J., Chinese Chemical Letters, 6:857 (1995); Mitscher, L. A., et al., J. Med. Chem., 30:2283 (1987).
The entire disclosures of the publications and references referred to above and hereafter in this specification are incorporated herein by reference.
The present invention is directed to novel compounds, pharmaceutical compositions, and methods for modulating processes mediated by steroid receptors. More particularly, the invention relates to non-steroidal compounds and compositions that are high-affinity, high-specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for the androgen receptor (AR). Also provided are methods of making and using such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.
In another aspect of the invention, a stereoselective synthetic route to intermediate compounds for these AR modulators is described. This aspect of the invention relates to preparing N-alkylated amino alcohol intermediates stereoselectively.
These and various other advantages and features of novelty that characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. The following detailed description of the invention provides a better understanding of the invention, its advantages, and objects obtained by its use, as well as preferred embodiments of the invention.
In accordance with the present invention, we have developed novel compounds, compositions, and methods of preparation of non-steroidal compounds that are AR modulators. Specifically, we have developed high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for the androgen receptor and methods of preparing these compounds and compositions.
In accordance with the present invention and as used herein, the following structure definitions are provided for nomenclature purposes. Furthermore, in an effort to maintain consistency in the naming of compounds of similar structure but differing substituents, the compounds described herein are named according to the following general guidelines. The numbering system for the location of substituents on such compounds is also provided.
The term xe2x80x9calkylxe2x80x9d refers to an optionally substituted straight-chain or branched-chain hydrocarbon radical having from 1 to about 10 carbon atoms, more preferably from 1 to about 6 carbon atoms, and most preferably from 1 to about 4 carbon atoms. Examples of alkyl radical include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having from 2 to about 10 carbon atoms, preferably from 2 to about 6 carbon atoms, and most preferably from 2 to about 4 carbon atoms. Preferred alkenyl groups include allyl. Examples of alkenyl radicals include ethenyl, propenyl, 1,4-butadienyl and the like.
The term xe2x80x9callylxe2x80x9d refers to the radical CH2xe2x95x90CHxe2x80x94CH2.
The term xe2x80x9calkynylxe2x80x9d refers to a straight-chain or branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having from 2 to about 10 carbon atoms, preferably from 2 to about 6 carbon atoms, and most preferably from 2 to about 4 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, butynyl and the like.
The term aryl refers to optionally substituted aromatic ring systems. The term aryl includes monocyclic aromatic rings, polycyclic aromatic ring systems, and polyaromatic ring systems. The polyaromatic and polycyclic ring systems may contain from two to four, more preferably two to three, and most preferably two, rings.
The term xe2x80x9cheteroarylxe2x80x9d refers to optionally substituted aromatic ring systems having one or more heteroatoms such as, for example, oxygen, nitrogen and sulfur. The term heteroaryl may include five- or six-membered heterocyclic rings, polycyclic heteroaromatic ring systems, and polyheteroaromatic ring systems where the ring system has from two to four, more preferably two to three, and most preferably two, rings. The terms heterocyclic, polycyclic heteroaromatic, and polyheteroaromatic include ring systems containing optionally substituted heteroaromatic rings having more than one heteroatom as described above (e.g., a six membered ring with two nitrogens), including polyheterocyclic ring systems from two to four, more preferably two to three, and most preferably two, rings. The term heteroaryl includes ring systems such as, for example, pyridine, quinoline, furan, thiophene, pyrrole, imidazole and pyrazole.
The term xe2x80x9calkoxyxe2x80x9d refers to an alkyl ether radical wherein the term alkyl is defined as above. Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9caryloxyxe2x80x9d refers to an aryl ether radical wherein the term aryl is defined as above. Examples of aryloxy radicals include phenoxy, benzyloxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety has about 3 to about 8 carbon atoms. Examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical having from about 3 to about 8 carbon atoms.
The term xe2x80x9carylalkylxe2x80x9d refers to an alkyl radical as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like. Preferably, arylalkyl refers to arylmethyl.
The terms alkyl, alkenyl, and alkynyl include optionally substituted straight-chain, branched-chain, cyclic, saturated and/or unsaturated structures, and combinations thereof.
The terms cycloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl include optionally substituted cycloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups.
The terms haloalkyl, haloalkenyl and haloalkynyl include alkyl, alkenyl and alkynyl structures, as described above, that are substituted with one or more fluorines, chlorines, bromines or iodines, or with combinations thereof.
The terms heteroalkyl, heteroalkenyl and heteroalkynyl include optionally substituted alkyl, alkenyl and alkynyl structures, as described above, in which one or more skeletal atoms are oxygen, nitrogen, sulfur, or combinations thereof.
The substituents of an xe2x80x9coptionally substitutedxe2x80x9d structure include, for example, one or more, preferably one to four, more preferably one to two, of the following preferred substituents: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkyl, cycloalkylalkyl, arylalkyl, amino, alkylamino, dialkylamino, F, Cl, Br, I, CN, NO2, NR10R11, NHCH3, N(CH3)2, SH, SCH3, OH, OCH3, OCF3, CH3, CF3, C(O)CH3, CO2CH3, CO2H and C(O)NH2, C1-C4 alkyl, C1-C4 haloalkyl, C3-C8 cycloalkyl, C1-C4 heteroalkyl, and OR9.
A 2H-1,4-benzoxazin-3(4H)-one is represented by the following structure: 
A 2H-1,4-benzoxazin is represented by the following structure: 
A 7H-[1,4]oxazino[3,2-g]quinolin-7-one is represented by the following structure: 
A 1H-[1,4]oxazino[3,2-g]quinoline is represented by the following structure: 
A 1H-[1,4]oxazino[3,2-g]quinoline-2(3H)-one is represented by the following structure: 
A 3H-[1,4]oxazino[3,2-g]quinolin-2,7-dione is represented by the following structure: 
A pyrido[1xe2x80x2,2xe2x80x2:4,5][1,4]oxazino[3,2-g]quinolin-9(8H)-one is represented by the following structure: 
A 1H-pyrrolo[1xe2x80x2,2xe2x80x2:4,5][1,4]oxazino[3,2-g]quinolin-8(7H)-one is represented by the following structure: 
A quinoxalin-2(1H)-one is represented by the following structure: 
A quinoxaline is represented by the following structure: 
A pyrazino[3,2-g]quinolin-2,7-dione is represented by the following structure: 
A pyrazino[3,2-g]quinolin-7(6H)-one is represented by the following structure: 
Compounds of the present invention are represented by those having the formulas: 
wherein:
R1 represents hydrogen, F, Cl, Br, I, NO2, OR9, NR10R11, S(O)mR9, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted;
R2 is hydrogen, F, Cl, Br, I, CF3, CF2H, CFH2, CF2OR9, CH2OR9, OR9, S(O)mR9, NR10R11, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted;
R3 is hydrogen, F, Cl, Br, I, OR9, S(O)mR9, NR10R11, or C1-C6 alkyl, C1-C6 heteroalkyl, or C1-C6 haloalkyl and wherein the alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted;
R4 and R5 each independently are hydrogen, OR9, S(O)mR9, NR10R11, C(Y)OR11, C(Y)NR10R11, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted; or
R4 and R5 taken together can form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted;
R6 and R7 each independently are hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted; or
R6 and R7 taken together can form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted; or
R6 and R5 taken together can form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted;
R8 is hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 haloalkyl, F, Cl, Br, I, NO2, OR9, NR10R11 or S(O)mR9, wherein the alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted;
R9 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C2-C8 alkenyl or arylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups may be optionally substituted;
R10 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C2-C8 alkenyl, arylalkyl, SO2R12 or S(O)R12, wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups may be optionally substituted;
R11 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C2-C8 alkenyl or arylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups may be optionally substituted;
R12 is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C2-C8 alkenyl or arylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkenyl and arylalkyl groups may be optionally substituted;
R13 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, or arylalkyl, wherein the alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl and arylalkyl groups may be optionally substituted; or
R13 and R4 taken together can form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted;
R14 and R15 each independently are hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, heteroaryl, arylalkyl, C2-C8 alkynyl or C2-C8 alkenyl, wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl and alkenyl groups may be optionally substituted;
RA is F, Br, Cl, I, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, OR16, NR16R17, SR16, CH2R16, COR17, CO2R17, CONR17R17, SOR17 or SO2R17, wherein the alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted;
R16 is hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 heteroalkyl, COR17, CO2R17 or CONR17R17, wherein the alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted;
R17 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 heteroalkyl, wherein the alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted;
m is 0, 1 or 2;
n is 1 or 2;
V is O, S or CR14R15;
W is O, S(O)m, NR13, NC(Y)R11, or NSO2R11
X and Z each independently are O, S(O)m, NR11, NC(Y)R11, NSO2R12 or NS(O)R12;
Y is O or S; and
any two of R4, R5, R6, R7, and R13 taken together can form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted;
and pharmaceutically acceptable salts thereof.
Preferred R1 groups include hydrogen, F, Cl, Br, I, NO2, OR9, NR10R11, S(O)mR9, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, allyl, C1-C8 aryl, C1-C8 arylalkyl, C1-C8 heteroaryl, C2-C8 alkynyl, and C2-C8 alkenyl. The alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R1 groups include H, F, Cl, OR9, NR10R11, S(O)mR9, and C1-C2 alkyl. Particularly preferred R1 groups include H, F, and Cl.
Preferred R2 groups include hydrogen, F, Cl, Br, I, CF3, CF2Cl, CF2H, CFH2, CF2OR9, CH2OR9, OR9, S(O)mR9, NR10R11, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8, heteroalkyl, C1-C8 haloalkyl, allyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl. The alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R2 groups include H, F, Cl, methyl, ethyl, CF3, CF2H, CF2Cl, CFH2, and OR9. Particularly preferred R2 groups include H, Cl, methyl, ethyl, CF3, CF2H, CF2Cl.
Preferred R3 groups include hydrogen, F, Cl, Br, I, OR9, S(O)mR9, NR10R11, C1-C6 alkyl, C1-C6 heteroalkyl and C1-C6 haloalkyl. The alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted. More preferred R3 groups include hydrogen, F, Cl, OR9, NR10R11, and S(O)mR9.
Preferred R4 groups include H, OR9, C(Y)OR11, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroaryl groups may be optionally substituted. More preferred R4 groups include H, OR9, C(Y)OR11, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 haloalkyl, C2-C4 alkynyl, and C2-C4 alkenyl. Particularly preferred R4 groups include H, OR9, C(Y)OR11, C1-C4 alkyl, C1-C4 haloalkyl, and where R4 and R13 together form a five- or six-membered ring.
Also preferred are compounds where R4 and R13 together form a saturated or unsaturated three- to seven-membered ring optionally substituted with 1-2 substituents. Examples of such substituents include, for example, hydrogen, F, Cl, Br, C1-C4 alkyl, C3-C8 cycloalkyl, C1-C4 heteroalkyl, C1-C4 haloalkyl, OR9 and NR10R11. The alkyl, cycloalkyl, heteroalkyl, haloalkyl groups may be optionally substituted.
Also preferred are compounds where R4 and R13 together form a five- to seven-membered ring optionally substituted with 1-2 substituents. Examples of such substituents include F, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 haloalkyl, and OR9. The alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted.
Preferred R5 groups include H, OR9, C(Y)OR11, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroaryl groups may be optionally substituted. More preferred R5 groups include hydrogen, OR9, C(Y)OR11, C1-C4 alkyl, and C1-C4 haloalkyl.
Also preferred are compounds where R4 and R5 taken together form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted.
Preferred R6 groups include hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, allyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl and heteroaryl. The alkyl, cycloalkyl, allyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroaryl groups may be optionally substituted. More preferred R6 groups include hydrogen, CH3, and CH2CH3.
Also preferred are compounds where R6 and R5 taken together form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted.
Preferred R7 groups include hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl and heteroaryl. The alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkynyl, alkenyl, aryl, arylalkyl and heteroaryl groups may be optionally substituted. More preferred R7 groups include hydrogen, CH3, and CH2CH3.
Also preferred are compounds where R6 and R7 taken together form a saturated or unsaturated three- to seven-membered ring that may be optionally substituted.
Preferred R8 groups include hydrogen, F, Cl, Br, I, NO2, OR9, S(O)mR9, C1-C4 alkyl, C1-C4 heteroalkyl, C1-C4 haloalkyl, and NR10OR11. The alkyl, heteroalkyl and haloalkyl groups may be optionally substituted. More preferred R8 groups include hydrogen and F.
Preferred R9 groups include hydrogen, C(Y)R12, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, arylalkyl, C2-C8 alkynyl and C2-C8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R9 groups include hydrogen, C(Y)R12, and C1-C6 alkyl. Particularly preferred R9 groups include CH3, CH2CH3, CH2CH2CH3, and C(O)CH3.
Preferred R10 groups include hydrogen, C(Y)R12, C(Y)OR12, SO2R12, S(O)R12, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, arylalkyl, C2-C8 alkynyl, and C2-C8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R10 groups include hydrogen, C1-C6 alkyl, C(Y)R12, C(Y)OR12, SO2R12.
Preferred R11 groups include hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, arylalkyl, C2-C8 alkynyl, and C2-C8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R11 groups include hydrogen and C1-C4 alkyl.
Preferred R12 groups include hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, allyl, arylalkyl, C2-C8 alkynyl, C2-C8 alkenyl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, allyl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R12 groups include hydrogen and C1-C4 alkyl.
Preferred R13 groups include hydrogen, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, C2-C8 alkynyl, and C2-C8 alkenyl. The alkyl, heteroalkyl, haloalkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R13 groups include C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 heteroalkyl and C1-C4 haloalkyl. Particularly preferred R13 groups include CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2(CH3), CH2(cyclopropyl), CH2CClF2, CH2CHF2, and CH2CF3.
Preferred R14 groups include hydrogen, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R14 groups include hydrogen and C1-C4 alkyl.
Preferred R15 groups include hydrogen, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, aryl, arylalkyl, and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, arylalkyl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R15 groups include hydrogen and C1-C4 alkyl.
Preferred R16 groups include hydrogen, C1-C8 alkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, C2-C8 alkynyl, C2-C8 alkenyl, COR17, CO2R17, CONR17R17, aryl, and heteroaryl. The alkyl, heteroalkyl, haloalkyl, aryl, heteroaryl, alkynyl, and alkenyl groups may be optionally substituted. More preferred R16 groups include hydrogen and C1-C4 alkyl.
Preferred RA groups include hydrogen, F, Cl, Br, I, CN, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, OR16, NR16R17, SR16, CH2R16, COR17, CO2R17, CONR17R17, SOR17, and SO2R17. The alkyl, heteroalkyl, and haloalkyl groups may be optionally substituted. More preferred RA groups include hydrogen, F, Cl, CN, and OR16.
Preferably n is 1 or 2. More preferably, n is 1.
Preferably, m is 1 or 2. More preferably, m is 1.
Preferred V groups include O and S. More preferably, V is O.
Preferred W groups include O, S(O)m, NR13, NC(Y)R11, and NSO2R11. More preferred W groups include NR13, NC(Y)R11, and NSO2R11. Particularly preferred W groups include NR13.
Preferred X groups include O, S(O)m, NR11, NC(Y)R11, NSO2R12 and NS(O)R12. More preferred X groups include O, S(O)m, and NR11. Particularly preferred X groups include O and S(O)m. Most preferably, X is O.
Preferably Y is O.
Preferred Z groups include O, S(O)m, NR11, NC(Y)R11, NSO2R12 and NS(O)R12. More preferred Z groups include O, S(O)m, and NR11. Most preferably, Z is NH.
In one aspect, compounds of formula I are preferred.
In another aspect, compounds of formula II are preferred.
In still another aspect, compounds of formula III are preferred.
In yet another aspect, compounds of formula IV are preferred.
In one preferred aspect, R3 and R8 are each hydrogen; X and Y are each independently O or S; W is NR13; and Z is NR11.
In another preferred aspect, R3 and R8 are each hydrogen; X and Y are each O, W is NR13; and Z is NR11.
In still another preferred aspect, R3 and R8 are each hydrogen; R2 is CF3, X and Y are each O, W is NR13; and Z is NR11.
In yet another preferred aspect, R1 R3, R4, R5, R6, R7, R8, R11 and RA are each hydrogen, R2 is CF3, R13 is C1-C8 alkyl, W is NR13, Z is NR11, X and Y are each O; and m is 1 or 2.
In yet another preferred aspect, R1 R3, R6, R7, R8, R11 and RA are each hydrogen, R2 is CF3, R4, R5 and R13 are each C1-C8 alkyl, W is NR13, Z is NR11, X and Y are each O; and m is 1 or 2.
In yet another preferred aspect, R1 R3, R4, R5, R8, R11 and RA are each hydrogen, R2 is CF3, R6, R7 and R13 are each C1-C8 alkyl, W is NR13, Z is NR11, X and Y are each O; and m is 1 or 2.
In a preferred aspect, the present invention provides a pharmaceutical compositions comprising an effective amount of an androgen receptor modulating compound of formulas I through VI shown above wherein R1 through R17, RA, V, W, X, Y, Z, m and n all have the same definitions as given above.
In a further preferred aspect, the present invention comprises methods of modulating processes mediated by androgen receptors comprising administering to a patient an effective amount of a compound of the formulas I through VI shown above, wherein R1 through R17, RA, V, W, X, Y, Z, m and n all have the same definitions as those given above.
Any of the compounds of the present invention can be synthesized as pharmaceutically acceptable salts for incorporation into various pharmaceutical compositions. As used herein, pharmaceutically acceptable salts include, for example, hydrochloric, hydrobromic, hydroiodic, hydrofluoric, sulfuric, citric, maleic, acetic, lactic, nicotinic, succinic, oxalic, phosphoric, malonic, salicylic, phenylacetic, stearic, pyridine, ammonium, piperazine, diethylamine, nicotinamide, formic, urea, sodium, potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino, methanesulfonic, picric, tartaric, triethylamino, dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically acceptable salts are known to those skilled in the art.
AR agonist, partial agonist and antagonist compounds (including compounds with tissue-selective AR modulator activity) of the present invention will prove useful in the treatment of acne (antagonist), male-pattern baldness (antagonist), male hormone replacement therapy (agonist), wasting diseases (agonist), hirsutism (antagonist), stimulation of hematopoiesis (agonist), hypogonadism (agonist), prostatic hyperplasia (antagonist), osteoporosis (agonist) male contraception (agonist), impotence (agonist), sexual dysfunction (agonist), cancer cachexia (agonist), various hormone-dependent cancers, including, without limitation, prostate (antagonist) and breast cancer and as anabolic agents (agonist). It is understood by those of skill in the art that a partial agonist may be used where agonist activity is desired, or where antagonist activity is desired, depending upon the AR modulator profile of the particular partial agonist.
It is understood by those skilled in the art that while the compounds of the present invention will typically be employed as a selective agonists, partial agonists or antagonists, that there may be instances where a compound with a mixed steroid receptor profile is preferred. For example, use of a PR agonist (i.e., progestin) in female contraception often leads to the undesired effects of increased water retention and acne flare-ups. In this instance, a compound that is primarily a PR agonist, but also displays some AR and MR modulating activity, may prove useful. Specifically, the mixed MR effects would be useful to control water balance in the body, while the AR effects would help to control any acne flare-ups that occur.
Furthermore, is understood by those skilled in the art that the compounds of the present invention, including pharmaceutical compositions and formulations containing these compounds, can be used in a wide variety of combination therapies to treat the conditions and diseases described above. Thus, the compounds of the present invention can be used in combination with other hormones and other therapies, including, without limitation, chemotherapeutic agents such as cytostatic and cytotoxic agents, immunological modifiers such as interferons, interleukins, growth hormones and other cytokines, hormone therapies, surgery and radiation therapy.
Representative AR modulator compounds (i.e., agonists and antagonists) according to the present invention include: 
Compounds of the present invention, comprising classes of heterocyclic nitrogen compounds and their derivatives, can be obtained by routine chemical synthesis by those skilled in the art, e.g., by modification of the heterocyclic nitrogen compounds disclosed or by a total synthesis approach.
The sequences of steps for several general schemes to synthesize the compounds of the present invention are shown below. In each of the schemes the R groups (e.g., R1, R2, etc.) correspond to the specific substitution patterns noted in the Examples. However, it will be understood by those skilled in the art that other functionalities disclosed herein at the indicated positions of compounds of formulas I through VI also comprise potential substituents for the analogous positions on the structures within the schemes.
The synthesis of 7H-[1,4]oxazino[3,2-g]quinolin-7-one compounds (e.g., Structures 6 and 7), is depicted in Scheme I. The process of Scheme I begins with a cyclization of a haloacetyl halide onto 2-amino-5-nitrophenol (Structure 1) with, for example, chloroacetyl chloride to afford a lactam (Structure 2). See D. R. Shridhar, et al., Org. Prep. Proc. Int., 14:195 (1982). The amide is then reduced to the corresponding amine (Structure 3), with, for example, borane dimethyl sulfide. See Y. Matsumoto , et. al., Chem. Pharm. Bull., 44:103-114 (1996). Treatment of a compound such as Structure 3 with an aldehyde or its corresponding hydrate or hemiacetal, for example trifluoroacetaldehyde hydrate in the presence of a reducing agent, for example, sodium cyanoborohydride, in a carboxylic acid, for example trifluoroacetic acid, affords a compound such as Structure 4. The nitro derivative is reduced to the corresponding aniline, with a reducing agent, for example, zinc and calcium chloride, to afford Structure 5. Treatment of the aniline with a xcex2-ketoester or corresponding hydrate, for example 4,4,4-trifluoroacetoacetate, at elevated temperatures, followed by treatment with an acid, for example, sulfuric acid, affords a major product (Structure 6). The cyclization of anilines as described above is known as a Knorr cyclization. See, G. Jones, Comprehensive Heterocyclic Chemistry, Katritzky, A. R.; Rees, C. W., eds. Pergamon, New York, 1984. Vol. 2, chap. 2.08, pp 421-426, the disclosure of which is herein incorporated by reference. In turn, the quinolinone nitrogen may be alkylated by, for example, treatment with sodium hydride followed by iodomethane, to afford a compound of Structure 7. Alternatively, a quinolinone compound of Structure 6 can be converted to the corresponding quinoline by treatment with a dehydrating agent, for example, oxyphosphoryl chloride, to afford a compound of Structure 7A.
Alternatively, a quinolinone compound of Structure 6 can be transformed to the corresponding thio-compound by treatment with, for example, Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] to give a 7H-[1,4]oxazino[3,2-g]quinolin-thione (e.g., Structure 8). See J. Voss, Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A., Ed. John Wiley and Sons, New York, 1995; Vol. 1, pp 530-533, the disclosure of which is herein incorporated by reference. Alternatively, a compound of Structure 6 (or chiral synthetic precursors of Structure 6) can be separated into its corresponding enantiomers, (+)-6 and (xe2x88x92)-6 by chiral HPLC, with, for example, a preparative Chiralpak AD column eluted with hexanes:isopropanol. 
An alternate synthesis of 7H-[1,4]oxazino[3,2-g]quinolin-7-one compounds (e.g., Structures 10 and 11) is shown in Scheme II. The process of Scheme II begins with a Knorr cyclization of 7-amino-3,4-dihydro-4-p-methoxybenzyl-2H-1,4-benzoxazine, and a xcex2-ketoester promoted by an acid, for example, sulfuric acid to afford a compound of Structure 10. Alkylation of the quinolinone nitrogen may be achieved by treatment with an aldehyde or its corresponding hydrate, for example cyclopropanecarboxaldehyde in the presence of a reducing agent, for example, sodium cyanoborohydride, to afford the alkylated derivative of the corresponding quinolinone compound (e.g., Structure 11). 
An additional synthetic route into quinoline compounds (e.g., Structures 16 and 18) is shown in Scheme III. The process of Scheme III begins with reductive amination of 2-methoxy-4-nitroaniline with an aldehyde or its corresponding hydrate, for example trifluoroacetaldehyde hydrate in the presence of a reducing agent, for example, sodium cyanoborohydride, in an acid, for example trifluoroacetic acid, to afford the corresponding N-alkylated amine. The nitro derivative is reduced to the corresponding aniline, with a reducing agent, for example, zinc and calcium chloride, to afford a compound of Structure 13. Knorr cyclization of the aniline by heating with a xcex2-ketoester or corresponding hydrate, for example 4,4,4-trifluoroacetoacetate, followed by treatment with an acid, for example, sulfuric acid, affords a product of Structure 14. Protection of the pyridone ring, with, for example isopropyl iodide mediated by a base, for example, cesium fluoride, affords the corresponding imino ether. See T. Sato, et al., Synlett 1995, 845-846. Demethylation of the anisole is accomplished by treatment with, for example, sodium thiophenolate to afford a compound of Structure 15. See C. Hansson, et al., Synthesis 1975, 191. Treatment of aminophenol derivative 15 with an xcex1-bromoester, for example, ethyl bromoacetate, and a base, with for example, potassium carbonate, affords a quinolinone compound (Structure 16). Treatment of quinolinone compounds such as Structure 16 with an alkylidenation reagent, for example, Tebbe""s reagent, followed by reduction with, for example, sodium cyanoborohydride, in an acid, for example acetic acid, affords a quinoline compound (e.g., Structure 17). See S. H. Pine, et. al., J. Org. Chem. 1985, 50, 1212, for the methylenation of amides. Deprotection can be accomplished in one of two ways. Treatment of the iminoether (Structure 17) with a mineral acid, for example hydrochloric acid, affords a 7H-[1,4]oxazino[3,2-g]quinolin-7-one compound (Structure 18). Alternatively, this transformation can be carried out with a Lewis acid, for example boron trichloride, to afford Structure 18. See T. Sala, et al., J. Chem. Soc., Perkin Trans. I, 1979, 2593. Quinolinone compounds of Structure 18 (or any chiral synthetic precursor of 18) can be separated into their corresponding enantiomers, (+)-18 and (xe2x88x92)-18 by chiral HPLC, with, for example, a preparative Chiralpak AD column eluted with hexanes:isopropanol. 
The process of converting quinolinone compounds (e.g., Structure 16) into corresponding hydroxyalkyl quinoline compounds (e.g., Structure 19) and then further converting into corresponding hydroxyalkyl, acyloxyalkyl, and alkyloxyalkyl quinolinone derivatives (e.g., Structures 20, 21, and 23 respectively) is shown in Scheme IV. The process of Scheme IV begins with a Tebbe olefination of a quinolinone compound (e.g., Structure 16) followed by hydroboration of the resultant enamine to afford a hydroxyalkyl quinoline compound (Structure 19). See C. T. Goralski, et. al. Tetrahedron Lett. 1994, 35, 3251, for the hydroboration of enamines. Hydrolysis of the imino ether with an acid, for example hydrochloric acid, affords a hydroxy quinolinone compound (e.g., Structure 20).
Alternatively, hydrolysis of the imino ether of a hydroxyalkyl quinoline compound (e.g., Structure 19) can be carried out with an acid, for example hydrochloric acid, in acetic acid, to afford an acyloxyalkyl quinolinone compound (Structure 21)
Alternatively, a hydroxy quinoline compound (e.g., Structure 19) can be O-alkylated by treatment with a base, for example, sodium hydride, and an alkylating agent, with, for example methyl iodide, to afford an alkoxyalkyl quinoline compound (e.g., Structure 22). Imino ether hydrolysis of Structure 22 with an acid, for example hydrochloric acid in acetic acid, affords an alkoxyalkyl quinoline compound (Structure 23). Compound such as Structures 20, 21, or 23 can be separated into their corresponding enantiomers, (+)-20 and (xe2x88x92)-20, (+)-21 and (xe2x88x92)-21, or (+)-23 and (xe2x88x92)-23 by chiral HPLC, with, for example, a preparative Chiralpak AD column eluted with hexanes:isopropanol. 
Quinolinone compounds (e.g., Structure 16) may be converted into corresponding quinoline-diones (e.g., Structure 24), hydroxy quinolinones (e.g., Structure 25), and quinoline-thiones (e.g., Structures 26 and 27) by the processes shown in Scheme V. The process of Scheme V begins with the deprotection of the imino ether of Structure 16 by treatment with a mineral acid, for example, hydrochloric acid, to afford a quinoline-dione compound of Structure 24. Alternatively, this transformation can be carried out with a Lewis acid, for example, boron trichloride, to afford a quinoline-dione compound (e.g., Structure 24). See T. Sala, et al., supra. A quinoline-dione compound (e.g., Structure 24) can be converted to a hydroxy quinoline compound (e.g., Structure 25) by addition of an organometallic reagent, for example, methyl lithium, which affords a hydroxy quinoline compound (Structure 25).
Quinoline compounds (e.g., Structure 16) can optionally be converted into corresponding thio-compounds (e.g., Structure 25) by treatment with, for example, Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]. Hydrolysis of the imino ether with a Lewis acid, for example, boron trichloride, affords a quinoline-thione compound (Structure 26). 
A synthesis of quinolinone compounds such as Structure 30 is shown in Scheme VI. The process of Scheme VI begins with the O-alkylation of an o-aminophenol, for example, a 6-amino-7-hydroxyquinoline, with a haloketone, for example, chloroacetone, mediated by a base, for example, potassium carbonate, followed by treatment with a reducing agent, for example, sodium cyanoborohydride, in an acid, for example, acetic acid, to afford a quinoline compound of Structure 29. Hydrolysis of the imino ether of Structure 29 with an acid, for example, hydrochloric acid in acetic acid, affords a quinolinone compound of Structure 30. Alkylation of the quinolinone nitrogen is achieved by treatment of quinolinone compounds (e.g., Structure 30) with an aldehyde or its corresponding hydrate, for example, cyclopropanecarboxaldehyde, with a reducing agent, for example, sodium cyanoborohydride, in an acid, for example, acetic acid, affords a compound of Structure 31. 
An additional route to quinolinone compounds such as Structure 31D is shown in Scheme VIA. The process of Scheme VIA begins with the alkylation of a 6-aminoquinolinone with, for example, 6-amino-7-methoxy-4-trifluoromethyl-1H-quinolin-2-one, with an alkyl halide, for example, isopropyl iodide, mediated by a base, for example, cesium fluoride, to afford a compound of structure 31B. Demethylation of the methyl ether is accomplished by treatment with, for example, sodium thiophenolate to afford a compound of Structure 31C. Annulation of the oxazine ring can be accomplished by treatment with a vicinal dihalide, for example, 1,2-dibromoethane, mediated by a base, for example potassium carbonate, to afford the corresponding 1,4-oxazine, which in turn is converted to a compound of Structure 31D by treatment with an acid, for example, hydrochloric acid in acetic acid at elevated temperatures. 
Quinolinones (e.g., Structure 35) are prepared from benzoxazines (e.g., Structure 34) by the synthetic route outlined in Scheme VII. Scheme VII begins with an alkylation of a haloketone onto 2-amino-5-nitrophenol (Structure 1) with, for example, 2-bromobutanone, mediated by a base, for example, potassium carbonate, followed by treatment with a reducing agent, for example, sodium cyanoborohydride, in an acid, for example acetic acid, to afford a benzoxazine compound (e.g., Structure 32). The benzoxazine is alkylated at the benzoxazine nitrogen by treatment of a benzoxazine compound (e.g., Structure 32) with an aldehyde, its corresponding hydrate or hemiacetal, with for example, trifluoroacetaldehyde hydrate in the presence of a reducing agent, for example, sodium cyanoborohydride, in an acid, for example trifluoroacetic acid. This procedure affords an alkylated benzoxazine compound (e.g., Structure 33). The nitro derivative of the alkylated benzoxazine compound (Structure 33) is reduced to the corresponding aniline by catalytic hydrogenation or with a reducing agent, for example, zinc and calcium chloride, to afford benzoxazine compound (e.g., Structure 34). Knorr cyclization of an aminobenzoxazine (e.g., Structure 34) by heating with a xcex2-ketoester or corresponding hydrate, with for example, 4,4,4-trifluoroacetoacetate, followed by treatment with an acid, for example, sulfuric acid, affords a quinolinone product (e.g., Structure 35). 
Compounds such as the 3,4-dihydro-7-nitro-2H-1,4-benzoxazines of Structure 33 are key intermediates in the preparation of quinolinones and other fused ring structures. In accordance with the current invention, we have developed a method to prepare these 3,4-dihydro-7-nitro-2H-1,4-benzoxazines in enantiomerically pure form (Structure 39) from optically pure xcex2-aminoalcohols. A synthetic method for the preparation of enantiomerically pure, fused ring compounds, such as quinolinones 41, that relies upon such intermediates is shown in Scheme VIII. 
The asymmetric synthesis of Scheme VIII begins with the chemo- and regioselective N-alkylation of a xcex2-aminoalcohol, either as a single enantiomer (R or S) or its racemate, for example, (R)-2-amino-1-propanol, onto a 3,4-dihalonitrobenzene, for example, 3,4-difluoronitrobenzene, mediated by a base, for example, sodium bicarbonate, affords an optically pure arylamino alcohol (e.g., Structure 36). Treatment of amino alcohol compounds such as Structure 36 with an aldehyde or the corresponding hydrate or hemiacetal, for example, trifluoroacetaldehyde ethyl hemiacetal, in the presence of an acid catalyst, for example p-toluenesulfonic acid, affords an optically pure oxazolidine compound (e.g., Structure 37). Treatment of an oxazolidine compound such as Structure 37 with a reducing agent, for example, triethylsilane, in the presence of an acid, for example, boron trifluoride etherate, affords an N-alkyl substituted amino alcohol compound (e.g., Structure 38). Benzoxazine compounds (e.g., Structure 39), may then be formed by cyclization of the N-alkyl substituted amino alcohol compounds (e.g., Structure 38) by treatment with a base such as sodium hydride. Reduction of nitro benzoxazine compounds (e.g., Structure 39) with a reducing agent, for example, zinc and calcium chloride affords an amino benzoxazine compound (e.g., Structure 40). Treatment of an amino benzoxazine with a xcex2-ketoester or its corresponding hydrate, for example ethyl 4,4,4-trifluoroacetoacetate, at elevated temperatures, affords the corresponding acetanilide. Treatment of the acetanilide with an acid, for example, sulfuric acid, affords an optically pure quinolinone compound (e.g., Structure 41). An enantiomer of Structure 41, or a racemic mixture may be obtained by the synthetic route as described in Scheme VIII, by starting with the enantiomer of the xcex2-aminoalcohol as shown (e.g., an (S)-xcex2-amino alcohol), or a racemic mixture of the xcex2-aminoalcohol shown (e.g., a (xc2x1)-xcex2-amino alcohol. Accordingly, an (S)-xcex2-amino alcohol, employed in Scheme VII, produces an (S)-quinolinone, an (R)-xcex2-amino alcohol, employed in Scheme VII, produces an (R)-quinolinone, and a racemic mixture of the xcex2-amino alcohol, employed in Scheme VII, produces a racemic mixture of the corresponding quinolinone.
Introduction of an N-alkyl or N-methylaryl group through the reductive cleavage of oxazolidine 37, as outlined in Scheme VIII, is generally applicable to the preparation of enantiomerically pure arylamino alcohol compounds such as Structure 38. Furthermore, the introduction of an N-(2-haloethyl) group through the reductive cleavage of an aryl oxazolidine is a novel process that has general utility in organic synthesis.

In the above process sequence, R4-7 may optionally represent hydrogen or alkyl or aryl groups, including C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C1-C4 alkyl, or C1-C4 haloalkyl;
RX may represent C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 heteroalkyl, C1-C8 haloalkyl, allyl, aryl, arylalkyl, heteroaryl, C2-C8 alkynyl, or C2-C8 alkenyl and wherein the alkyl, cycloalkyl, heteroalkyl, haloalkyl, allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl are optionally substituted with halogen, C1-C4 alkyl, or C1-C4 haloalkyl.
Ar represents optionally substituted aryl or heteroaryl groups, including mono- and polycyclic structures, optionally substituted at one or more positions.
Additional substitutions are also possible and can be readily determined by one skilled in the art.
The above process sequence begins with an arylamino alcohol which is then converted into an oxazolidine with an aldehyde or the corresponding hydrate or hemiacetal in the presence of an acid catalyst. The oxazolidine is then converted to an N-alkylarylamino alcohol by addition of a reducing agent such as triethylsilane or sodium cyanoborohydride in the presence of a Lewis acid such as boron trifluoride etherate or a protic acid such as trifluoroacetic acid as a catalyst. Additional aldehydes and their corresponding hydrates as well as reducing agents may be used and are readily determined by those skilled in the art. 
Scheme IX describes an alternative to the route of Scheme VIII for formation of enantiomerically pure benzoxazine compounds such as Structure 39. The route of Scheme IX offers direct access to compounds of Structure 39 in which R4 and R13 taken together form a ring structure. The process of Scheme IX begins with reaction of a secondary aminoalcohol, either a single enantiomer (R or S) or its racemate, for example 2-piperidinemethanol, with a 3,4-dihalonitrobenzene, for example, 3,4-difluoronitrobenzene, to afford an N-aryl substituted tertiary aminoalcohol compound such as Structure 42. Cyclization of Structure 42, mediated by treatment with a base, for example, sodium hydride, affords a benzoxazine compound (e.g., Structure 39). Benzoxazine compounds such as Structure 39 may then further be employed in the synthesis of quinolinone compounds as described herein. 
Pyrazino-quinolinone compounds (e.g., Structure 49) may be prepared by the process described in Scheme X. The process of Scheme X begins with the alkylation of a 1,2-phenylenediamine, for example, 1,2-phenylenediamine, with an xcex1-haloester, for example ethyl 2-bromoisobutyrate, mediated by a base, for example diisopropylethylamine, to afford a compound of Structure 44. Nitration of 44 with, for example, nitric acid in sulfuric acid, affords a compound of Structure 45. The nitro group of 45 can be reduced to the corresponding aniline, with, for example, palladium on carbon under a hydrogen atmosphere, to afford a compound of Structure 46. Treatment of the aniline with a xcex2-ketoester or its corresponding hydrate, for example 4,4,4-trifluoroacetoacetate, at elevated temperatures, affords the corresponding acetanilide. Treatment of the acetanilide with an acid, for example, sulfuric acid, affords a compound of Structure 47. Protection of the pyridone ring, with, for example isopropyl iodide mediated by a base, for example, cesium fluoride, affords the corresponding imino ether (Structure 48). Reduction of the amide with, for example, borane dimethyl sulfide, affords the corresponding amine. Hydrolysis of this imino ether with an acid, for example, hydrochloric acid in acetic acid, affords a pyrazino-quinolinone compound such as Structure 49. 
Thiazino-quinolinone compounds (e.g., Structure 56) are prepared as shown in Scheme XI. The process of Scheme XI begins with the treatment of an aniline, for example, 4-bromo-3-chloroaniline, with a xcex2-ketoester or its corresponding hydrate, for example 4,4,4-trifluoroacetoacetate, at elevated temperatures, to afford the corresponding acetanilide. Treatment of the acetanilide with an acid, for example, sulfuric acid, affords the corresponding 1H-quinolin-2-one (an example of a Knorr cyclization as described further herein). Protection of the pyridone ring, with, for example, isopropyl iodide, mediated by a base, for example, cesium fluoride, affords a compound of Structure 51. Treatment of a compound (e.g., Structure 51) with a xcex2-aminothiol, for example, 2-aminoethanethiol hydrochloride, mediated by a base, for example, sodium hydride, affords a compound of Structure 52. Treatment of a compound of Structure 52 with a ligated transition metal. for example palladium acetate and BINAP, in the presence of a base, for example sodium t-butoxide, at elevated temperatures, affords a compound of Structure 53, See S. Wagaw, et al., J. Am. Chem. Soc. 1997, 119, 8451-8458. Treatment of a compound of Structure 53 with an aldehyde or its corresponding hydrate or hemiacetal, for example, formaldehyde, affords a compound of Structure 55. Hydrolysis of the imino ether can be accomplished by treatment of a compound of Structure 55 with an acid, for example hydrochloric acid, at elevated temperatures, to afford a thiazino-quinolinone compound such as Structure 56. Alternatively, a compound of Structure 53 can be deprotected with an acid, for example hydrochloric acid, at elevated temperatures, to afford a thiazino-quinolinone compound such as Structure 54.
The compounds of the present invention also include racemates, stereoisomers and mixtures of said compounds, including isotopically-labeled and radio-labeled compounds. Such isomers can be isolated by standard resolution techniques, including fractional crystallization and chiral column chromatography.
As noted above, any of the steroid modulator compounds of the present invention can be combined in a mixture with a pharmaceutically acceptable carrier to provide pharmaceutical compositions useful for treating the biological conditions or disorders noted herein in mammalian, and more preferably, in human patients. The particular carrier employed in these pharmaceutical compositions may take a wide variety of forms depending upon the type of administration desired, e.g., intravenous, oral, topical, suppository or parenteral.
In preparing the compositions in oral liquid dosage forms (e.g., suspensions, elixirs and solutions), typical pharmaceutical media, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets and capsules), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like will be employed. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage form for the pharmaceutical compositions of the present invention.
For parenteral administration, the carrier will typically comprise sterile water, although other ingredients that aid in solubility or serve as preservatives, may also be included. Furthermore, injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like will be employed.
For topical administration, the compounds of the present invention may be formulated using bland, moisturizing bases, such as ointments or creams. Examples of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin, and water in oil emulsions such as Eucerin(trademark) (Beiersdorf). Examples of suitable cream bases are Nivea(trademark) Cream (Beiersdorf), cold cream (USP), Purpose Cream(trademark) (Johnson and Johnson), hydrophilic ointment (USP), and Lubriderm(trademark) (Warner-Lambert).
The pharmaceutical compositions and compounds of the present invention will generally be administered in the form of a dosage unit (e.g., tablet, capsule etc.) at from about 1 xcexcg/kg of body weight to about 500 mg/kg of body weight, more preferably from about 10 xcexcg/kg to about 250 mg/kg, and most preferably from about 20 xcexcg/kg to about 100 mg/kg. As recognized by those skilled in the art, the particular quantity of pharmaceutical composition according to the present invention administered to a patient will depend upon a number of factors, including, without limitation, the biological activity desired, the condition of the patient, and tolerance for the drug.
The compounds of this invention also have utility when radio- or isotopically-labeled as ligands for use in assays to determine the presence of AR in a cell background or extract. They are particularly useful due to their ability to selectively activate androgen receptors, and can therefore be used to determine the presence of such receptors in the presence of other steroid receptors or related intracellular receptors.
Due to the selective specificity of the compounds of this invention for steroid receptors, these compounds can be used to purify samples of steroid receptors in vitro. Such purification can be carried out by mixing samples containing steroid receptors with one or more of the compounds of the present invention so that the compounds bind to the receptors of choice, and then separating out the bound ligand/receptor combination by separation techniques which are known to those of skill in the art. These techniques include column separation, filtration, centrifugation, tagging and physical separation, and antibody complexing, among others.
The compounds and pharmaceutical compositions of the present invention can advantageously be used in the treatment of the diseases and conditions described herein. In this regard, the compounds and compositions of the present invention will prove particularly useful as modulators of male sex steroid-dependent diseases and conditions such as the treatment of acne, male-pattern baldness, male hormone replacement therapy, sexual dysfunction, wasting diseases, hirsutism, stimulation of hematopoiesis, hypogonadism, prostatic hyperplasia, osteoporosis, male contraception, impotence, cancer cachexia, various hormone-dependent cancers, including, without limitation, prostate and breast cancer and as anabolic agents.
The compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroidal and non-steroidal compounds.
Furthermore, the compounds and pharmaceutical compositions of the present invention possess a number of advantages over previously identified steroid modulator compounds. For example, the compounds are extremely potent activators of AR, preferably displaying 50% maximal activation of AR at a concentration of less than 100 nM, more preferably at a concentration of less than 50 nM, more preferably yet at a concentration of less than 20 nM, and most preferably at a concentration of 10 nM or less. Also, the selective compounds of the present invention generally do not display undesired cross-reactivity with other steroid receptors, as is seen with the compound mifepristone (RU486; Roussel Uclaf), a known PR antagonist that displays an undesirable cross reactivity on GR and AR, thereby limiting its use in long-term, chronic administration. In addition, the compounds of the present invention, as small organic molecules, are easier to synthesize, provide greater stability and can be more easily administered in oral dosage forms than other known steroidal compounds.